Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses

Qiuhui Li, Qu Deng, Hsueh-Ping Chao, Xin Liu, Yue Lu, Kevin Lin, Bigang Liu, Gregory W. Tang, Dingxiao Zhang, Amanda Tracz, Collene Jeter, Kiera Rycaj, Tammy Calhoun-Davis, Jiaoti Huang, Mark A. Rubin, Himisha Beltran, Jianjun Shen, Gurkamal Chatta, Igor Puzanov, James L. Mohler, Jianmin Wang, Ruizhe Zhao, Jason Kirk, Xin Chen () and Dean G. Tang ()
Additional contact information
Qiuhui Li: Roswell Park Comprehensive Cancer Center
Qu Deng: Roswell Park Comprehensive Cancer Center
Hsueh-Ping Chao: University of Texas M.D. Anderson Cancer Center
Xin Liu: University of Texas M.D. Anderson Cancer Center
Yue Lu: University of Texas M.D. Anderson Cancer Center
Kevin Lin: University of Texas M.D. Anderson Cancer Center
Bigang Liu: University of Texas M.D. Anderson Cancer Center
Gregory W. Tang: University of Texas M.D. Anderson Cancer Center
Dingxiao Zhang: Roswell Park Comprehensive Cancer Center
Amanda Tracz: Roswell Park Comprehensive Cancer Center
Collene Jeter: University of Texas M.D. Anderson Cancer Center
Kiera Rycaj: Roswell Park Comprehensive Cancer Center
Tammy Calhoun-Davis: University of Texas M.D. Anderson Cancer Center
Jiaoti Huang: Duke University of School of Medicine
Mark A. Rubin: Weill Cornell Medical College
Himisha Beltran: Weill Cornell Medical College
Jianjun Shen: University of Texas M.D. Anderson Cancer Center
Gurkamal Chatta: Roswell Park Comprehensive Cancer Center
Igor Puzanov: Roswell Park Comprehensive Cancer Center
James L. Mohler: Roswell Park Comprehensive Cancer Center
Jianmin Wang: Roswell Park Comprehensive Cancer Center
Ruizhe Zhao: Roswell Park Comprehensive Cancer Center
Jason Kirk: Roswell Park Comprehensive Cancer Center
Xin Chen: Roswell Park Comprehensive Cancer Center
Dean G. Tang: Roswell Park Comprehensive Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR−/lo). Xenograft modeling demonstrates that AR+ CRPC is enzalutamide-sensitive but AR−/lo CRPC is resistant. Genome editing-derived AR+ and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR+/hi and AR−/lo CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR−/lo PCa cells/clones.

Date: 2018
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DOI: 10.1038/s41467-018-06067-7

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